The proopiomelanocortin peptide alpha-MSH regulates melanin production and growth of melanocytes by binding to and activating the MSH receptor. Recently we reported the cloning of the genes encoding the human and murine MSH receptors. Three additional related receptors, the receptor for ACTH, and two unique neural melanocortin receptors (MC30R & MC4-R) that recognize a variety of ACTH and MSH peptides were also clone and characterized. The murine MSH receptor (MSH-R) was subsequently found to map to the distal portion of chromosome 8 in the mouse near a gene locus affecting pigmentation, called extension. Variant extension locus alleles in the mouse were found to result from point mutation s which alter MSH recaptor function. In mice, the recessive yellow extension allele (e) results from a frameshift producing a prematurely terminated non-functioning receptor. The sombre (Eso & Eso-31) and tobacco darkening (Eob) alleles, which both have dominant melanizing effects, result from point mutations which produce hyperactive MSH receptors. The Eso-eJ receptor is constitutively activated, while the Eob receptor remains hormone responsive, and produces a greater activation of its effector, adenylyl cyclase, than does the wild type allele. The extension locus is an homologous gene locus for which variant alleles have been described in many mammalian species. We propose to characterize variant MSH-R/extension alleles in man and other mammals to determine the general role of these alleles in man will be designed to identify correlations with skin, hair, and eye color, melanoma susceptibility, and other pigmentation disorders. Study of the MSH receptor will not only further our understanding of pigmentation; this receptor is perhaps one of the best models for the study of G protein coupled peptide receptor structure and activation. The MSH receptor is the only known G protein coupled with naturally occurring functional variants. The cloning of four melanocortin receptor with differing ligand specificities (MSH-R, ACH-R, MC3-R,MC$-R) and the natural occurrence of MSH receptors with variable activity also provide a unique resource for the study of G protein coupled receptors. Data obtained from cloning nd characterization of variant MSH-R alleles, from biochemical and in vitro mutagenesis studies of the MSH receptor, and from characterization of other POMC receptors will also be used to develop a detailed model of the structure and activation of this receptor.